Meir Mouallem

Pseudohypoparathyroidism, a Novel Mutation in the βγ-Contact Region of Gsα Impairs Receptor Stimulation

Pseudohypoparathyroidism, type Ia (PHP-Ia), is a dominantly inherited endocrine disorder characterized by resistance to hormones that act by stimulating adenylyl cyclase. It is caused by inheritance of an autosomal mutation that inactivates the α subunit (αs) of Gs, the stimulatory regulator of adenylyl cyclase. In three members of a family, the PHP-Ia phenotype is associated with a mutation (R231H) that substitutes histidine for an arginine at position 231 in αs. We assessed signaling function of αs-WT versus αs-R231H transiently transfected in HEK293 cells. Hormone receptor-dependent stimulation of cAMP accumulation in cells expressing αs-R231H is reduced by ∼75% in comparison to cAMP accumulation in cells expressing αs-WT. A second mutation, αs-R201C, inhibits the GTPase turnoff reaction of αs, thus producing receptor-independent stimulation of cAMP accumulation. The double mutant, αs-R231H/R201C, stimulates cAMP accumulation almost as well (∼80%) as does αs-R201C itself, indicating that the R231H mutation selectively impairs receptor-dependent signaling. In three-dimensional structures of G protein heterotrimers, Arg-231 is located in a region, switch 2, that is thought to interact with the βγ subunit rather than with the hormone receptor. Thus, the R231H phenotype suggests that switch 2 (perhaps in concert with βγ) mediates G protein activation by receptors at a site distant from the receptor-G protein contact surface.

Clinical characteristics and risk factors for low dose methotrexate toxicity: a cohort of 28 patients.

OBJECTIVE Low dose (10-25 mg/week) methotrexate is widely used for the management of systemic inflammatory diseases, and is considered to be relatively safe. Toxicity due to low dose MTX has been reported but is poorly characterized. We describe the clinical features, risk factors, and outcomes of low dose MTX toxicity in a large case series at our center. PATIENTS AND METHODS We conducted a retrospective case series of all adult (>18 years) patients hospitalized at Sheba Medical Center, between 2005 and 2012 for low dose MTX toxicity. RESULTS We identified 28 patients (age: 70.4±13.7 years, range: 33-88; 20 (71%) females) hospitalized for low dose MTX toxicity. Indications for MTX therapy included: rheumatoid arthritis (39.2%), psoriasis±arthritis (21.5%), polymyalgia rheumatica (10.8%) and other inflammatory conditions (28.5%). Pancytopenia was the most common manifestation of low dose MTX toxicity detected in 78.5% of the patients. Potential risk factors included acute renal failure, hypoalbuminemia, concurrent use of drugs known to interact with MTX, and dose errors. Serum MTX concentrations (n=20, mean 0.04±0.07 μg/mL range: 0-0.3) did not correlate with the degree of either neutropenia (r=-0.36; p=0.18) or thrombocytopenia (r=0.44; p=0.10). Seven (25%) patients died, all from pancytopenia followed by sepsis. Serum MTX concentrations did not differ between the patients who died from MTX toxicity (n=6; mean: 0.05±0.04 μg/mL) and those who survived the toxicity (n=14 mean 0.04±0.08; p=0.45). CONCLUSIONS Low-dose MTX toxicity can be life threatening, mainly due to myelosuppression. There is no rationale for MTX therapeutic drug monitoring in the setting of low-dose toxicity.

Pseudohypoparathyroidism type Ia: two new heterozygous frameshift mutations in exons 5 and 10 of the Gsα gene

Pseudohypoparathyroidism type Ia (PHP-Ia) is a hereditary disease characterized by resistance to PTH and other hormones that act via cAMP. Patients have deficient activity of Gsα, the α subunit of the G protein, which couples hormone receptors to stimulation of adenylate cyclase. We describe two new mutations discovered in two sporadic patients with PHP-Ia. Using genomic DNA, we have amplified exons 2–13 of the Gsα gene (GNAS1) by PCR, and sequenced the resulting products. Both patients had Albrights hereditary osteodystrophy, resistance to multiple hormones, and deficient Gsα activity. In the first patient, a deletion of a C in exon 5 at codon 115 was found. In the second patient, an insertion of a C in exon 10 at codon 267 was detected. Both these heterozygous mutations cause frameshift, and predict decreased production of Gsα. This report adds two new Gsα mutations to the known ten mutations recently described.

Clopidogrel-induced systemic inflammatory response syndrome

Clopidogrel bisulfate, a widely used inhibitor of platelet aggregation, is considered at least as safe as aspirin. We describe a patient who developed a systemic inflammatory response syndrome consisting of high fever, tachycardia, cellulitis-like rash, impaired liver function, and mild leukopenia after receiving clopidogrel before coronary angiography and stent implantation. The reaction resolved promptly after withdrawal of the drug and recurred shortly after a rechallenge dose was administered, thus making the diagnosis of a clopidogrel-induced reaction highly probable. Recognition of this clopidogrel-induced syndrome is extremely important, both for rapid discontinuation of the offending drug and for avoidance of unnecessary drug therapy or invasive procedures.

Adult celiac disease presented with celiac crisis: severe diarrhea, hypokalemia, and acidosis.

An acute severe onset of celiac disease is very uncommon in adults. We describe a patient with adult celiac disease who presented with acute diarrhea that lead rapidly to a life threatening hypokalemia and acidosis, the so-called celiac crisis. Celiac crisis, described mainly in children younger than two years of age, has become very rare due to earlier diagnosis and effective therapy of the disease. The case described is an example of the heterogeneous clinical course of celiac disease and emphasizes the need to consider it in the differential diagnosis, even in adults suffering from acute diarrhea and acidosis.

Pericardial Tamponade-Associated Hyponatremia

We describe a 58-year-old patient with adenocarcinoma of the lung who suffered from severe weariness that was attributed to hyponatremia. The cause of hyponatremia was found to be a malignant pericardial effusion that caused pericardial tamponade. The hyponatremia was corrected rapidly after the evacuation of the malignant effusion. The pathogenetic mechanisms of hyponatremia secondary to pericardial effusion are discussed.

Acute Kidney Injury, Hepatitis, and CPK Elevation Associated With Nitrofurantoin Therapy

Nitrofurantoin is a commonly used antibiotic for the treatment of urinary tract infections. We present a case in which nitrofurantoin was suspected to be the cause of acute interstitial nephritis combined with elevated liver enzymes and CPK.

A man with a prosthetic valve, anaemia, fever, and splenomegaly

Vitamin B12 deficiency was found to be the cause of all three manifestations of the patient’s disease: anaemia, fever, and splenomegaly. Fever occurring in vitamin B12 deficiency is usually not mentioned in current texts, even being omitted from the recent edition of Harrison’s principles of internal medicine. In the era before vitamin B12 treatment, fever was recorded in up to 79% of patients with pernicious anaemia, and in Davidson’s series it occurred in 22% of patients. Davidson related the degree and frequency of fever to the severity of the anaemia, and stated that pyrexia disappears when blood supply to the cerebral heat regulatory centres is improved by blood transfusion or after B12 therapy. McKee, who found that fever was present in about 40% of patients with megaloblastic anaemia, suggested that it was caused by the increased activity of the megaloblastic bone marrow. In most patients with vitamin B12 deficiency and fever, the elevation of temperature is mild, although there are patients with temperatures of above 38·5°C. In our patient, fever persisted after blood transfusion with an elevation of Hb to 10·1 g/dL, and resolved only after B12 administration. Splenomegaly found in our patient is also a manifestation of B12 deficiency; reported in 27% of Cabot’s patients, in 8% of Davidson’s patients, and in 25% of Hall’s patients. Although the mechanism of fever in B12 deficiency is unknown, its occurrence is not rare, and physicians should note this important sign of a curable disease.

Rickettsiosis-associated hyponatremia.

Two patients with hyponatremia (130 mEq/l and 122 mEq/l, respectively), and rickettsial disease are described. The causes of hyponatremia were attributed to rickettsial vasculitis and increased capillary permeability in the first patient and to the syndrome of inappropriate anti-diuretic hormone (ADH) secretion in the second patient. The differentiation between the mechanisms was established by measurement of urinary sodium excretion which was low in the first patient (7 mEq/l) and high in the second patient (60 mEq/l), and levels of ADH that were inappropriately high in the second patient (7–9 pg/ml) in the presence of low plasma osmolality. The differentiation between these causes of hyponatremia has important therapeutic implications. Es werden zwei Patienten beschrieben, die bei einer Rikkettsien-Infektion eine Hyponatriämie von 130 mÄq/l bzw. 122 mÄq/l entwickelten. Die Ursache für die Hyponatriämie wird beim ersten Patienten in einer Rikkettsien-Vaskulitis mit erhöhter Kapillarpermeabilität und beim zweiten in einer inadäquaten Sekretion von antidiuretischem Hormon (ADH) gesehen. Durch Messung der Natriumausscheidung im Urin war eine Differenzierung der beiden Pathomechanismen möglich: beim ersten Patienten war die Natriumausscheidung mit 7 mÄq/l niedrig und beim zweiten mit 60 mÄq/l hoch. Zudem waren die ADH-Spiegel beim zweiten Patienten mit 7–9 pg/ml bei geringer Plasmaosmolalität unangemessen hoch. Die Unterscheidung der Ursachen der Hyponatriämie hat wichtige therapeutische Konsequenzen.SummaryTwo patients with hyponatremia (130 mEq/l and 122 mEq/l, respectively), and rickettsial disease are described. The causes of hyponatremia were attributed to rickettsial vasculitis and increased capillary permeability in the first patient and to the syndrome of inappropriate anti-diuretic hormone (ADH) secretion in the second patient. The differentiation between the mechanisms was established by measurement of urinary sodium excretion which was low in the first patient (7 mEq/l) and high in the second patient (60 mEq/l), and levels of ADH that were inappropriately high in the second patient (7–9 pg/ml) in the presence of low plasma osmolality. The differentiation between these causes of hyponatremia has important therapeutic implications.ZusammenfassungEs werden zwei Patienten beschrieben, die bei einer Rikkettsien-Infektion eine Hyponatriämie von 130 mÄq/l bzw. 122 mÄq/l entwickelten. Die Ursache für die Hyponatriämie wird beim ersten Patienten in einer Rikkettsien-Vaskulitis mit erhöhter Kapillarpermeabilität und beim zweiten in einer inadäquaten Sekretion von antidiuretischem Hormon (ADH) gesehen. Durch Messung der Natriumausscheidung im Urin war eine Differenzierung der beiden Pathomechanismen möglich: beim ersten Patienten war die Natriumausscheidung mit 7 mÄq/l niedrig und beim zweiten mit 60 mÄq/l hoch. Zudem waren die ADH-Spiegel beim zweiten Patienten mit 7–9 pg/ml bei geringer Plasmaosmolalität unangemessen hoch. Die Unterscheidung der Ursachen der Hyponatriämie hat wichtige therapeutische Konsequenzen.

Prolonged Oral Morphine Therapy for Severe Angina Pectoris

Patients with intractable angina pectoris despite optimal drug therapy, who are not candidates for revascularization procedures, pose a very difficult problem. We evaluated the role of chronic opioid therapy in four such patients. The patients (mean age 79.5 years) were treated by low doses (mean 40 mg/day) of controlled-release oral morphine (CRM) for 1 to 5 years. The treatment was followed by a marked decline in the rate of admissions and hospitalization periods. The number of admissions decreased from a mean of 6 during the year prior to CRM therapy to 1.5 the following year. The duration of hospitalization for angina pectoris during these periods decreased from a mean of 42 +/- 35 days to 6 +/- 10 days (p < 0.05). Side effects were negligible and consisted mainly of lactulose-responsive constipation. We suggest that prolonged oral morphine therapy may be administered with good efficacy and no significant side effects in selected patients with intractable angina pectoris.